In this study, we report the poly ADP‐ribosylation (PARylation) of HMGA1 during DNA damage, leading to desensitization of esophageal squamous cell carcinoma (ESCC) cells to the poly(ADP‐ribose) polymerase 1 (PARP1) inhibitor, olaparib. This evidence concerns the gene PARP1 and esophageal squamous cell carcinoma.